EVALUATING NOVEL THERAPIES FOR NEURODEGENERATIVE DISEASES USING DROSOPHILA MODELS

Pathogenesis in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD), is linked to protein-protein and protein-RNA interactions. I evaluated previously identified potential therapies for ALS and AD using Drosophila models. The ALS project targeted Tar DNA-binding protein 43 (TDP-43), part of a DNA-binding protein family that forms toxic aggregates in motor neurons. The Q331K mutation in the C-terminal region is linked to familial ALS. The AD project targeted C-terminal ends of CD44 proteins bound by FERM proteins involved in inflammation. Biochemical and biophysical validation of in silico docking experiments identified three promising compounds. rTRD01 and nTRD022 target the TDP-43 RRM1 and N-terminal domains, respectively. Peptidomimetic01 targets the CD44:Radixin FERM interaction. ALS and AD are characterized by decreased lifespan, impaired motor function, and protein aggregation. We utilized survival curves, climbing assays, and quantification of protein aggregation to assess therapeutic potential. Our results found rTRD01 rescues TDP-43OE flies’ climbing, decreases TDP-43 aggregation in male TDP-43Q331K flies, rescues survival in TDP-43Q331K flies, and may rescue survival in TDP-43OE flies. nTRD022 was found to rescue TDP-43OE flies’ climbing and not affect TDP-43Q331K flies’ climbing. Early data indicate nTRD022 rescues survival in TDP-43Q331K and has no negative effect on TDP-43OE fly survival. Peptidomimetic01 displays rescue of Αβ42E693G flies’ climbing over time while not negatively affecting lifespan. These experiments established a workflow for screening therapeutic compounds in Drosophila models and show targeting protein:protein and protein:RNA interactions for drug discovery elucidates compounds that may be developed into ALS and AD therapeutics